Low proliferative activity in macroregenerative nodules: evidence for an alternate hypothesis concerning human hepatocarcinogenesis

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Abstract
Macroregenerative nodules are commonly thought to be hyperplastic lesions, deriving both their large size and premalignant potential from an increased proliferative rate. We have previously suggested an alternate model of macroregenerative nodule development in which neither size nor premalignant potential of macroregenerative nodules would depend on increased proliferation. We tested this hypothesis by examining the proliferative activity in macroregenerative and surrounding cirrhotic nodules. Methods: Eighteen macroregenerative nodules, including five type I and 13 type II, were immunostained for proliferating cell nuclear antigen (PCNA). Type II macroregenerative nodules included ten with diffuse large (7) or small (3) liver cell dysplasia only and eight containing nodule‐ in‐nodule lesions. Five nodule‐in‐nodule lesions met the histologic criteria for hepatocellular carcinoma. PCNA labeling indices (PCNA‐LIs; percentage positive hepatocyte nuclei/500 randomly counted cells) were determined in macroregenerative nodules and the four largest adjacent cirrhotic nodules. Nodule‐in‐nodule lesions were assessed separately from the background macroregenerative nodule. Results: 4/5 type I and 12/13 type II macroregenerative nodules (exclusive of NIN lesions) had PCNA‐LIs lower than the mean of surrounding cirrhotic nodules. All nodule‐in‐nodule lesions, whether atypical or overtly malignant, had PCNA‐LIs greater than any surrounding nodules. In conclusion, macroregenerative nodules have PCNA‐LIs indistinguishable from, and often lower than, surrounding cirrhotic nodules. Increased proliferative activity only occurs with the development of atypia and transition to hepatocellular carcinoma. Conclusion: Macroregenerative nodules derive neither their size nor their premalignant potential from on‐going rapid proliferation, a finding consistent with our alternate hypothesis of macroregenerative nodule development.